Lecture 6 Flashcards
Lupus
2 forms: discoid lupus which only affects the skin and SLE which affects skin and joints and frequently involves internal organs (e.g heart and kidneys)
Cardiovascular problems are the leading cause of death in SLE. Common problems are pericarditis and pleurisy with accelerated atherosclerosis
Symptoms include joint pains, rashes, extreme fatigue, fever and swelling of lymph glands
Causes of SLE
Runs in families but no single gene identified as causal, susceptibility genes are known
Numerous environmental triggers e.g. UV radiation and viral infection
Immune abnormalities associated with SLE
- defective clearing of apoptotic cells
- increased response to AGs containing nucleic acids
- decreased threshold of activation of autoAB producing Bcells
One theory is that defective clearing of apoptotic cells by macrophages results in APCs presenting apoptotic material as autoantigens resulting in anti-nuclear ABs (ANA) the main diagnostic tests for SLE involve blood tests against ANA and anti-dsDNA
Impaired NET degradation which would provide a further source of common SLE AGs such as histones
Increased levels of cytokines including TNFα, IL-6, interferons and B lymphocyte stimulator (BLyS important for B cell survival, differentiation and AB production)
Treatments for SLE
- NSAIDs to reduce joint pains and fever
- Hydroxychloroquine reduces inflammation likely by reducing interferon production
- corticosteroids to reduce inflammation in flare ups
- immunosuppressives e.g methotrexate and azathioprine
- belimumab, anti-BLyS, sequestration of BLyS reduces B cell activity
- Rituximab (limited trial evidence, many B cell subsets, CD20+ may not be that important in lupus)
When are immunosuppressive drugs used?
Autoimmune diseases and to avoid transplant rejection
How to corticosteroids exert an immunosuppressive effect?
Decrease the transcription of a variety of cytokines including those that drive Th proliferation (IL-2) and inflammatory responses (e.g. IL-1 and TNFα).
Also upregulate anti-inflammatory factors such as IL-1ra
Azathioprine
Prodrug for 6-mercaptopurine (6-MP) which is converted to thioinosic monophosphate (TIMP) by hypoxanthine phosphoribosyl transferase (HPRT)
TIMP converted to 2 different products
1. converted to 6-methyl-TIMP (MeTIMP) by thiopurine methyltransferase(TPMT). MeTIMP inhibits de novo purine synthesis
- converted to 6-thioguanosine nucleotides (6-TGN) via inosine monophosphate dehydrogenase (IMPDH). This inhibits nucleotide and protein synthesis
These effects inhibit cellular proliferation especially in cells that lack the ability to synthesise nucleotides from intermediates of nucleotide degradation such as T and B cells
Side effects of azathioprine
GI disturbance, bone marrow suppression and hepatotoxicity
Levels of TPMT vary, 10% of people have very low levels leading to accumulation of cytotoxic 6-thioguanine nucleotide and associated toxicity
can be prevented by monitoring TPMT levels
Methotrexate
Folic acid antagonist.
Targets rapidly proliferating cells such as immune cells and therefore can be used as an immunosuppressant
Mycophenolic acid
Derived from the fungus penicillum stoloniferum and inhibits IMPDH which is crucial for de novo synthesis of guanosine (greatest impact on B and T cells)
Mainly used in transplant rejections but also in autoimmune disease such as myasthenia gravis
Cyclophosphamide
Commonly used alkylating agent which is a prodrug
Converted to aldophosphamide by hepatic p450 enzymes
Then converted to active phosphoramide mustard which has 2 alkylating groups and cross links guanine in DNA via N7 groups
1) bischloroethylamine undergoes cyclisation releasing Cl- and forms an unstable immonium cation
2) the strained ring opens to form a reactive carbonium ion
3) carbonium ion reacts with guanine’s N7 to produce 7-alkylguanine
4) 7-alkylguanine pairs with thymine producing substitution of A-T for G-C
it can also induce guanine excision and chain breakage
This kills rapidly dividing T and B cells
Side effects of cyclophosphamide
Bone marrow suppression
Potential infertility
Bladder irritation (TRPA1)and cancer
Some other forms of cancer e.g. lymphoma
What is cyclophosphamide used to treat?
Refractory autoimmune conditions and some cancers
Cyclosporin A (CsA)
Immunosuppressant isolated from the fungus tolypocladium inflatum
CsA is a cyclic 11 amino acid peptide whose predominant action is to prevent T cell proliferation via suppression of IL-2 synthesis
CsA binds to a cytoplasmic protein called cyclophilin (CpN). The CsA-CpN complex binds to and inhibits calcineurin (a ser-thr phosphatase). This prevents the dephosphorylation of the nuclear factor of activated T cells (NF-AT) and therefore prevents it from entering the nucleus thus preventing IL-2 upregulation
Tacrolimus
A macrolide antibiotic
Binds to an immunophilin called FK-binding protein which in complex with tacrolimus inhibits calcineurin, thus NF-AT is retained and IL-2 upregulation is inhibited